Penicillin G

Pharmacologic Category

Antibiotic, Penicillin

Dosing: Adult

Usual dosage range: IM, IV: 12 to 24 million units/day in divided doses every 4 to 6 hours

Indication-specific dosing:

Actinomyces species: IV:

Cervicofacial disease: 1 to 6 million units/day in divided doses every 4 to 6 hours

Thoracic and abdominal disease: 10 to 20 million units/day in divided doses every 4 to 6 hours

Anthrax: IV: Minimum 8 million units/day in divided doses every 6 hours; higher doses may be required depending on the susceptibility of the organism.

Clostridium species: IV:

Botulism, gas gangrene, tetanus: 20 million units/day in divided doses every 4 to 6 hours; adjunctive therapies for botulism and tetanus (eg, botulinum antitoxin, tetanus immune globulin) are also recommended.

Skin and soft tissue necrotizing infections (off-label use): 2 to 4 million units every 4 to 6 hours; use in combination with clindamycin and continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014])

Cutibacterium acnes infection of deep-brain stimulation hardware (off-label use): IV: 24 million units/day in divided doses every 4 hours (IDSA [Tunkel 2017])

Diphtheria (adjunctive therapy to antitoxin and for prevention of carrier state): IV: 2 to 3 million units/day in divided doses every 4 to 6 hours for 10 to 12 days

Endocarditis, treatment: IV:

Enterococcus, native or prosthetic valve (penicillin-susceptible/gentamicin-susceptible strains) (off-label dose): 18 to 30 million units/day as continuous infusion or in divided doses every 4 hours with concomitant gentamicin. Duration of therapy: 4 weeks (native valve and symptoms present <3 months); 6 weeks (native valve and symptoms present ≥3 months or prosthetic valve) (AHA [Baddour 2015).

Enterococcus, native or prosthetic valve (penicillin-susceptible/streptomycin-susceptible/gentamicin-resistant strains) (off-label dose): 18 to 30 million units/day as continuous infusion or in divided doses every 4 hours with concomitant streptomycin. Duration of therapy: 4 weeks (native valve and symptoms present <3 months); ≥6 weeks (native valve and symptoms present ≥3 months or prosthetic valve) (AHA [Baddour 2015).

Erysipelothrix rhusiopathiae: 12 to 20 million units/day in divided doses every 4 to 6 hours for 4 to 6 weeks

Listeria monocytogenes: 15 to 20 million units/day in divided doses every 4 to 6 hours for 4 weeks

Viridans group streptococcus (VGS) and S. bovis (off-label dose) (AHA [Baddour 2015]):

Native valve: Highly penicillin-susceptible (MIC ≤0.12 mcg/mL): 12 to 18 million units/day as continuous infusion or in divided doses every 4 or 6 hours for 4 weeks or 12 to 18 million units/day as continuous infusion or in divided doses every 6 hours for 2 weeks with concomitant gentamicin

Native valve: Relatively penicillin-resistant (MIC >0.12 to <0.5 mcg/mL): 24 million units/day as continuous infusion or in divided doses every 4 or 6 hours for 4 weeks with concomitant gentamicin for the first 2 weeks

Prosthetic valve: Highly penicillin-susceptible (MIC ≤0.12 mcg/mL): 24 million units/day as continuous infusion or in divided doses every 4 or 6 hours for 6 weeks (with or without concomitant gentamicin for the first 2 weeks)

Prosthetic valve: Relatively or fully penicillin-resistant (MIC >0.12 mcg/mL): 24 million units/day as continuous infusion or in divided doses every 4 or 6 hours with concomitant gentamicin for 6 weeks

Fusospirochetosis (including Vincent disease): IV: 5 to 10 million units/day in divided doses every 4 to 6 hours

Leptospirosis (off-label use): IV: 1.5 million units every 6 hours for 7 days (Panaphut 2003; Suputtamongkol 2004; Watt 1988)

Lyme neuroborreliosis (off-label use): IV: 3 to 4 million units every 4 hours (Halperin 2007; Halperin 2013)

Meningitis, bacterial: As a component of pathogen-specific therapy (eg, Listeria monocytogenes, Neisseria meningitidis [with MIC <0.1 mcg/mL], Cutibacterium acnes, Streptococcus agalactiae, or Streptococcus pneumoniae [with MIC ≤0.06 mcg/mL]): IV: 4 million units every 4 hours (Hof 1997; IDSA [Tunkel 2004]; IDSA [Tunkel 2017]; Medoff 1971). In patients with meningitis due to Listeria, combination with an aminoglycoside is recommended (Drevets 1994; Hof 1997).

Neurosyphilis(including ocular syphilis): IV: 18 to 24 million units/day in divided doses every 4 hours (or by continuous infusion) for 10 to 14 days (CDC [Workowski 2015])

Osteomyelitis, native vertebral (off-label use) (IDSA [Berbari 2015]): IV:

Enterococcus spp (penicillin-susceptible) or streptococci (beta-hemolytic): 20 to 24 million units/day as a continuous infusion or in divided doses every 4 hours for 6 weeks. Note: In patients with infective endocarditis due to penicillin-susceptible Enterococcus spp, the addition of an aminoglycoside for 4 to 6 weeks is recommended.

Cutibacterium acnes: 20 million units/day as a continuous infusion or in divided doses every 4 hours for 6 weeks

Pasteurella infections (bacteremia, meningitis): IV: 4 to 6 million units/day in divided doses every 4 to 6 hours for 2 weeks

Prosthetic joint infection (off-label use): IV:

Enterococcus spp (penicillin-susceptible), streptococci (beta-hemolytic): 20 to 24 million units/day as a continuous infusion every 24 hours or in divided doses every 4 hours for 4 to 6 weeks (Osmon 2013); Note: For penicillin-susceptible Enterococcus spp, consider addition of aminoglycoside.

Cutibacterium acnes: 20 million units/day as a continuous infusion every 24 hours or in divided doses every 4 hours for 4 to 6 weeks (Osmon 2013)

Rat bite fever (including Haverhill fever): IV:

Uncomplicated infection: 200,000 units every 4 hours for 5 to 7 days; if patient clinically improves after initial IV course, may switch to oral therapy (eg, penicillin V, amoxicillin) to complete a 14 day course (CDC 2005; King 2017)

Serious invasive infection: 12 to 18 million units/day as a continuous infusion every 24 hours or in divided doses every 4 to 6 hours for 4 weeks; may increase dose to 24 million units/day in patients with an isolate that is not highly penicillin susceptible (King 2017)

Streptococcus infections: IV:

Group B streptococcus (GBS), maternal prophylaxis for prevention of neonatal disease (off-label use): Note: Prophylaxis is reserved for pregnant women with a positive GBS vaginal or rectal screening in late gestation or GBS bacteriuria during the current pregnancy, history of birth of an infant with early-onset GBS disease, and unknown GBS culture status with any of the following: birth <37 0/7 weeks gestation, intrapartum fever, prolonged rupture of membranes, known GBS positive in a previous pregnancy, or intrapartum nucleic acid amplification testing positive for GBS (ACOG 2019).

5 million units as a single dose at the onset of labor or prelabor rupture of membranes, then 3 million units every 4 hours until delivery (ACOG 2019).

Skin infections, including skin and soft tissue necrotizing infections (off-label use): 2 to 4 million units every 4 to 6 hours; use in combination with clindamycin for necrotizing infections and continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014])

Group A streptococcus invasive infection, severe: 3 to 4 million units every 4 hours with clindamycin for 10 to 14 days (Walker 2014)

Streptococcal pneumonia: IV: 12 to 24 million unit/day in divided doses every 4 to 6 hours. Note: Only recommended for S. pneumoniae when MIC is <2 mcg/mL (Mandell 2007).

Whipple disease (off-label use): IV: 2 to 4 million units every 4 hours for 2 to 4 weeks, followed by oral trimethoprim/sulfamethoxazole monotherapy or oral doxycycline and hydroxychloroquine for 1 year (Bures 2013)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

Manufacturer's labeling:

Uremic patients with CrCl >10 mL/minute/1.73 m2: Administer a usual recommended dose followed by 50% of the usual recommended dose every 4 to 5 hours

CrCl <10 mL/minute/1.73 m2: Administer a normal dose followed by 50% of the normal dose every 8 to 10 hours

Alternate recommendation:

GFR >50 mL/minute: No dosage adjustment necessary (Aronoff 2007).

GFR 10-50 mL/minute: Administer 75% of the normal dose (Aronoff 2007).

GFR <10 mL/minute: Administer 20% to 50% of the normal dose (Aronoff 2007).

End-stage renal disease on intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days) (Heintz 2009): Administer a normal dose followed by either 25% to 50% of normal dose every 4 to 6 hours or 50% to 100% of normal dose every 8 to 12 hours. For mild-to-moderate infections, administer 0.5 to 1 million units every 4 to 6 hours or 1 to 2 million units every 8 to 12 hours. For neurosyphilis, endocarditis, or serious infections, administer up to 2 million units every 4 to 6 hours; administer after dialysis on dialysis days or supplement with 500,000 units after dialysis. Note: Dosing dependent on the assumption of 3 times weekly, complete IHD sessions.

Continuous renal replacement therapy (CRRT) (Heintz 2009; Trotman 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1 to 2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH: Loading dose of 4 million units, followed by 2 million units every 4 to 6 hours

CVVHD: Loading dose of 4 million units, followed by 2 to 3 million units every 4 to 6 hours

CVVHDF: Loading dose of 4 million units, followed by 2 to 4 million units every 4 to 6 hours

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling. However, the manufacturer's labeling recommends further adjustment of doses adjusted for renal impairment in patients with both renal and hepatic impairment.

Dosing: Pediatric

General dosing, susceptible infection (Red Book [AAP 2015]): Infants, Children, and Adolescents:

Mild to moderate infection: IM, IV: 100,000 to 150,000 units/kg/day in divided doses every 6 hours; maximum daily dose: 8 million units/day

Severe infections: IM, IV: 200,000 to 300,000 units/kg/day in divided doses every 4 to 6 hours; maximum daily dose: 24 million units/day; Note: Use highest dose in range for CNS infections.

Anthrax, systemic; treatment:

Non-CNS infection; preferred agent for penicillin-susceptible strains: Infants, Children, and Adolescents: IV: 400,000 units/kg/day in divided doses every 4 hours; maximum dose: 4 million units/dose; use in combination with clindamycin, linezolid, doxycycline, or rifampin for ≥14 days until clinical stability is achieved (ie, appear well with no signs or symptoms of active infection and can tolerate oral therapy); treatment must be followed by prophylaxis for a total antibiotic course of 60 days (AAP [Bradley 2014])

Meningitis; preferred agent for penicillin-susceptible strains: Infants, Children, and Adolescents: IV: 400,000 units/kg/day in divided doses every 4 hours; maximum dose: 4 million units/dose; use in combination with a fluoroquinolone plus linezolid, clindamycin, rifampin, or chloramphenicol for ≥2 to 3 weeks until clinical stability is achieved (ie, appear well with no signs or symptoms of active infection and can tolerate oral therapy); treatment must be followed by prophylaxis for a total antibiotic course of 60 days (AAP [Bradley 2014])

Clostridial myonecrosis (gas gangrene): Infants, Children, and Adolescents: IV: 250,000 to 400,000 units/kg/day in divided doses every 4 to 6 hours with or without clindamycin (Red Book [AAP 2015])

Diphtheria: Infants, Children, and Adolescents: IM, IV: 150,000 to 250,000 units/kg/day in divided doses every 6 hours for 7 to 10 days. AAP suggests a duration of 14 days (Red Book [AAP 2015]).

Endocarditis, bacterial; treatment: Children and Adolescents: IV: 200,000 to 300,000 units/kg/day in divided doses every 4 hours; maximum daily dose: 24 million units/day; treat for at least 4 weeks; longer durations may be necessary; may use in combination with gentamicin for some resistant organisms (AHA [Baltimore 2015]). Note: For endocarditis from rat-bite fever/haverhill fever, the manufacturer recommends a lower dose of 150,000 to 250,000 units/kg/day in divided doses every 4 hours; maximum daily dose: 20 million units/day.

Lyme disease: Infants, Children, and Adolescents: IV: 200,000 to 400,000 units/kg/day in divided doses every 4 hours; maximum daily dose: 24 million units/day (AAN [Halperin 2007]; IDSA [Wormser 2006])

Meningitis: Note: Dosing varies based on organism being treated.

Group B streptococcus: Infants: IV: 450,000 to 500,000 units/kg/day divided every 6 hours (Red Book [AAP 2015])

S. pneumoniae: Infants, Children, and Adolescents: IV: 250,000 to 400,000 units/kg/day divided every 4 to 6 hours (Red Book [AAP 2015])

Other susceptible organisms: Infants, Children, and Adolescents: IV: 300,000 units/kg/day divided every 4 to 6 hours; maximum daily dose: 24 million units/day (IDSA [Tunkel 2004])

Meningococcal disease: Infants, Children, and Adolescents: IV: 300,000 units/kg/day in divided doses every 4 to 6 hours; maximum daily dose: 12 million units/day (Red Book [AAP 2015])

Pneumonia, community-acquired (CAP): Infants >3 months and Children:

Empiric treatment or S. pneumoniae (moderate to severe; MICs to penicillin ≤2.0 mcg/mL): IV: 200,000 to 250,000 units/kg/day divided every 4 to 6 hours (IDSA/PIDS [Bradley 2011])

Alternate dosing (AAP recommendation): IV: 250,000 to 400,000 units/kg/day divided every 4 to 6 hours (Red Book [AAP 2015])

Group A Streptococcus (moderate to severe): IV: 100,000 to 250,000 units/kg/day divided every 4 to 6 hours (IDSA/PIDS [Bradley 2011])

Skin and soft tissue necrotizing infections due to Clostridium species: Infants, Children, and Adolescents: IV: 60,000 to 100,000 units/kg/dose every 6 hours; use in combination with clindamycin and continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014])

Streptococcal skin infections, including skin and soft tissue necrotizing infections: Infants, Children, and Adolescents: IV: 60,000 to 100,000 units/kg/dose every 6 hours; maximum dose: 4 million units/dose; use in combination with clindamycin for necrotizing infections and continue until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours (IDSA [Stevens 2014])

Syphilis:

Congenital: Infants and Children: IV: 50,000 units/kg/dose every 4 to 6 hours for 10 days (CDC [Workowski 2015])

Neurosyphilis (including ocular syphilis):

Infants and Children: IV: 50,000 units/kg/dose every 4 to 6 hours for 10 to 14 days; maximum daily dose: 24 million units/day

Adolescents: IV: 3 to 4 million units every 4 hours or as a continuous infusion for 10 to 14 days; maximum daily dose: 24 million units/day (CDC [Workowski 2015])

Tetanus; treatment: Infants, Children, and Adolescents: IV: 100,000 units/kg/day in divided doses every 4 to 6 hours for 7 to 10 days; maximum daily dose: 12 million units/day (Red Book [AAP 2015])

Dosing: Renal Impairment: Pediatric

Manufacturer's labeling: Infants, Children, and Adolescents: IM, IV:

Uremic patients with CrCl >10 mL/minute/1.73 m2: Administer a normal dose followed by 50% of the normal dose every 4 to 5 hours

CrCl <10 mL/minute/1.73 m2: Administer a normal dose followed by 50% of the normal dose every 8 to 10 hours

Hemodialysis: Dialyzable

Dosing: Hepatic Impairment: Pediatric

All patients: There are no dosage adjustments provided in the manufacturer's labeling; however, the manufacturer's labeling recommends further adjustment of doses adjusted for renal impairment in patients with both renal and hepatic impairment.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Creatinine Clearance by Jelliffe
• Creatinine Clearance by Sanaka
• Glomerular Filtration Rate by Abbreviated MDRD
• Glomerular Filtration Rate by Abbreviated MDRD (SI units)
• Glomerular Filtration Rate by MDRD
• Glomerular Filtration Rate by MDRD (IDMS-Traceable SCr)
• Glomerular Filtration Rate by MDRD (SI units)
• Glomerular Filtration Rate by Schwartz
• Glomerular Filtration Rate Estimate in African Americans by AASK Equation

Use: Labeled Indications

Anthrax: Treatment of anthrax caused by Bacillus anthracis

Actinomycosis: Treatment of actinomycosis (cervicofacial disease and thoracic and abdominal disease) caused by Actinomyces israelii

Clostridial infections: Treatment of botulism (adjunctive therapy to antitoxin), gas gangrene, and tetanus (adjunctive therapy to human tetanus immune globulin) caused by Clostridium spp.

Diphtheria: Treatment of diphtheria (adjunctive therapy to antitoxin and prevention of the carrier state) caused by Corynebacterium diphtheriae

Erysipelothrix endocarditis: Treatment of erysipelothrix endocarditis caused by Erysipelothrix rhusiopathiae

Fusospirochetosis: Treatment of fusospirochetosis, including severe infections of the oropharynx [Vincent], lower respiratory tract and genital area, caused by Fusobacterium spp. and spirochetes

Listeria infections: Treatment of listeria infections, including meningitis and endocarditis, caused by Listeria monocytogenes

Meningococcal infection: Treatment of meningococcal meningitis and/or septicemia caused by Neisseria meningitidis

Pasteurella infections: Treatment of pasteurella infections, including bacteremia and meningitis, caused by Pasteurella multocida

Rat bite fever: Treatment of rat bite fever (including Haverhill fever) caused by Spirillum minus or S. moniliformis

Serious gram-positive infections: Treatment of septicemia, empyema, pneumonia, pericarditis, endocarditis, and meningitis caused by Streptococcus pyogenes (group A beta-hemolytic streptococcus), other beta-hemolytic streptococci including groups C, H, G, L and M, Streptococcus pneumoniae and Staphylococcus species (nonpenicillinase-producing strains)

Syphilis: Treatment of syphilis (congenital and neurosyphilis) caused by Treponema pallidum

Use: Off-Label: Adult

Cutibacterium acnes infection of deep-brain stimulation hardwareLevel of Evidence [G]

Based on the Infectious Diseases Society of America (IDSA) guidelines for the management of health-care associated ventriculitis and meningitis, penicillin G is an effective and recommended agent for infections of deep-brain stimulation hardware due to Cutibacterium acnes, an organism commonly associated with this type infection.

Group B streptococcus, maternal prophylaxis for prevention of neonatal diseaseLevel of Evidence [G]

Based on the American College of Obstetricians and Gynecologists (ACOG) prevention of group B streptococcal early-onset disease in newborns guideline, maternal administration of intravenous penicillin is the preferred antibiotic for intrapartum prophylaxis to prevent early onset group B streptococcal disease in the newborn.

LeptospirosisLevel of Evidence [A, G]

Based on the World Health Organization/International Leptospirosis Society guidance for Human Leptospirosis Diagnosis, Surveillance and Control, penicillin G (parenteral/aqueous) is an effective and recommended option for treatment of severe leptospirosis; in randomized controlled trials it is equal in efficacy to third generation cephalosporins or doxycycline Ref. Penicillin G (parenteral/aqueous), however, has the disadvantage of frequent parenteral administration and lack of coverage for common co-infections Ref.

Lyme neuroborreliosisLevel of Evidence [G]

Based on the American Academy of Neurology guidelines for the Diagnosis and Management of nervous system Lyme disease (ie, Lyme neuroborreliosis), penicillin G (parenteral/aqueous) is an effective option for treatment of this condition and has comparable rates of efficacy to ceftriaxone Ref.

Osteomyelitis, native vertebralLevel of Evidence [G]

Based on the Infectious Diseases Society of America (IDSA) guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults, penicillin G is an effective and recommended agent for the treatment of native vertebral osteomyelitis due to Enterococcus spp (penicillin-susceptible), beta-hemolytic streptococci, or Cutibacterium acnes.

Prosthetic joint infectionLevel of Evidence [G]

Based on the Infectious Diseases Society of America (IDSA) guidelines for the management of prosthetic joint infection, penicillin G (parenteral/aqueous) is an effective and recommended agent for the treatment of prosthetic joint infection with Enterococcus spp (penicillin-susceptible with or without an aminoglycoside), streptococci (beta-hemolytic) and Cutibacterium acnes.

Skin and soft tissue infectionsLevel of Evidence [G]

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), penicillin G (parenteral/aqueous) is an effective and recommended option for treatment of streptococcal skin infections; use in combination with clindamycin when treating necrotizing infections of the skin, fascia, and muscle due to Group A Streptococcus and/or Clostridium species.

Whipple DiseaseLevel of Evidence [C]

Data from a limited number of patients studied suggest that penicillin G (parenteral/aqueous) with or without concomitant antibiotics may be beneficial for the treatment of Whipple disease when parenteral treatment is warranted Ref. Additional data may be necessary to further define the role of penicillin G (parenteral/aqueous) in this condition. Clinical experience also suggests the utility of penicillin G (parenteral/aqueous) in the treatment of Whipple disease Ref.

Level of Evidence Definitions

Level of Evidence Scale

Use: Unsupported: Adult

Disseminated gonococcal infection

Based on CDC guidelines, penicillin G aqueous is no longer a recommended therapy for confirmed or presumptive treatment of disseminated gonococcal infection based on resistance in N. gonorrhoeae. (CDC [Workowski 2015])

Class and Related Monographs

Penicillins

Clinical Practice Guidelines

Infectious Endocarditis:

AHA, “Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications,” October 2015

Meningitis, Bacterial:

IDSA, “Practice Guidelines for the Management of Bacterial Meningitis,” November 2004

Meningitis and Ventriculitis, Healthcare-Associated:

IDSA, "Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis," February 2017.

Opportunistic Infection:

HHS, Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV

Osteomyelitis, Native Vertebral:

IDSA, "Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults," 2015

Perinatal Group B Streptococcal Disease:

ACOG, “Prevention of Group B Streptococcal Early-Onset Disease in Newborns”, 2019

Pneumonia, Community-Acquired:

ATS/IDSA, "Diagnosis and Treatment of Adults With Community-Acquired Pneumonia," 2019. Note: Information contained within this monograph is pending revision based on these more recent guidelines.

Prosthetic Joint Infection:

IDSA, “Diagnosis and Management of Prosthetic Joint Infection: Clinical Practice Guideline,” January 2013

Sexually Transmitted Disease:

CDC, “Sexually Transmitted Diseases Treatment Guidelines,” June 2015.

Public Health Agency of Canada, “Canadian Guidelines on Sexually Transmitted Infections," January 2010

World Health Organization (WHO), "Guidelines for the Treatment of Treponema pallidum (syphilis),” 2016

Skin and Soft-tissue Infection:

IDSA, “Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections,” June 2014

Vertebral Osteomyelitis:

IDSA, "Clinical Practice Guidelines for the Diagnosis and Treatment of Native Vertebral Osteomyelitis in Adults," July 2015

Administration: IM

Administer IM by deep injection in the upper outer quadrant of the buttock. Administer injection around-the-clock to promote less variation in peak and trough levels. Note: The 20 million unit dosage form may be administered by continuous IV infusion only.

Administration: IV

Usually administered by intermittent infusion. In some centers, large doses may be administered by continuous IV infusion. Note: The 20 million unit dosage form may be administered by IV infusion only.

Intermittent IV: Infuse over 15 to 30 minutes.

Administration: Injectable Detail

pH: 6-7.5

Administration: Pediatric

Parenteral:

IM: Administer IM by deep injection in the upper outer quadrant of the buttock. Administer injection around-the-clock to promote less variation in peak and trough levels.

IV: Usually administered by intermittent infusion. In some centers, large doses may be administered by continuous IV infusion. The potassium or sodium content of the dose should be considered when determining the infusion rate.

Intermittent IV: Infuse over 15 to 30 minutes

Continuous IV infusion: Daily dose may be administered as a continuous infusion over 24 hours, or smaller increments (eg, 24 hour dose divided into two 12-hour infusions)

Dietary Considerations

Some products may contain potassium and/or sodium.

Storage/Stability

Penicillin G potassium powder for injection should be stored below 86°F (30°C). Following reconstitution, solution may be stored for up to 7 days under refrigeration. Premixed bags for infusion should be stored at -20°C or -4°F; frozen bags may be thawed at 25°C (77°F) or in a refrigerator (5°C [41°F]). Once thawed, solution is stable for 14 days at 5°C (41°F) or for 24 hours at 25°C (77°F). Do not refreeze once thawed.

Penicillin G sodium powder for injection should be stored at 20°C to 25°C (68°F to 87°F). Once reconstituted, the manufacturer recommends refrigeration (2°C to 8°C [36°F to 46°F]) and use within 3 days of reconstitution. After further dilution to 2,500 to 50,000 units/mL in either D5W or NS (in PVC bags or elastomeric pump containers), one study demonstrated stability when stored under refrigeration for up to 21 days (Hossain 2014).

Preparation for Administration: Adult

Intermittent IV infusion: 5 million unit vial: Add 8.2 mL SWFI or NS for a final concentration of 500,000 units/mL; add 3.2 mL for a final concentration of 1,000,000 units/mL. Dilute further to 50,000 to 145,000 units/mL prior to infusion.

Continuous IV infusion: 20 million unit vial: Add 11.5 mL SWFI or NS for a final concentration of 1,000,000 units/mL. Dilute further in 1 to 2 L of infusion solution and administer over a 24-hour period.

Intramuscular: 5 million unit vial: Add 8.2 mL SWFI or NS for a final concentration of 500,000 units/mL; add 3.2 mL for a final concentration of 1,000,000 units/mL. Dilute further, up to 100,000 units/mL, for less discomfort. If larger doses are needed, consider IV infusion.

Intrapleural: If fluid is aspirated, administer local infusion in a volume equal to 25 to 50% of the amount of fluid aspirated. If fluid is not aspirated, prepare as directed for IM injection and infuse locally.

Preparation for Administration: Pediatric

Parenteral:

IM: 5 million unit vial: Solutions containing ≤100,000 units/mL may be used with minimal discomfort

IV:

Intermittent IV infusion: 5 million unit vial: Reconstitute powder for injection with SWFI, NS, or D5W to a resultant concentration of 500,000 to 1,000,000 units/mL (see manufacturer's labeling for specific details). Further dilute in an appropriate fluid to usual final concentration range of 50,000 to 100,000 units/mL prior to infusion. In fluid-restricted patients, ~150,000 units/mL in SWFI results in a maximum recommended osmolality for peripheral infusion (Robinson 1987). In neonates a concentration of 25,000 units/mL has been used (Prober 1990).

Continuous IV infusion: 20 million unit vial: Add 11.5 mL for a resultant concentration of 1,000,000 units/mL. Determine the volume of an appropriate fluid and rate of its administration (the potassium content of the dose should be considered when determining the infusion rate) required by the patient in a 24-hour period. Add the appropriate daily dosage of penicillin to this fluid. For example, if the daily dose is 10 million units and 2 L of fluid/day is required, add 5 million units to 1 L and adjust the rate of flow so the liter will be infused over 12 hours (83 mL/hour). Repeat steps (5 million units/L at 83 mL/hour) for the remaining 12 hours.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat bacterial infections.

Frequently reported side effects of this drug

• Diarrhea

• Nausea

• Vomiting

• Mouth irritation

• Mouth sores

• Tongue discoloration

• Injection site irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• High potassium like abnormal heartbeat, confusion, dizziness, passing out, weakness, shortness of breath, numbness or tingling feeling

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Severe dizziness

• Passing out

• Chills

• Sore throat

• Headache

• Fast heartbeat

• Fast breathing

• Flushing

• Severe loss of strength and energy

• Yellow skin or eyes

• Muscle pain

• Joint pain

• Abdominal pain

• Bruising

• Bleeding

• Twitching

• Seizures

• Unable to pass urine

• Change in amount of urine passed

• Numbness

• Tingling

• Weakness

• Clostridioides (formerly Clostridium) difficile-associated diarrhea like stomach pain or cramps, very loose or watery stools, or bloody stools.

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Contraindications

Hypersensitivity to any penicillin or any component of the formulation

Documentation of allergenic cross-reactivity for beta-lactams (eg, penicillins and cephalosporins) is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactic/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity (including cephalosporins) or history of sensitivity to multiple allergens. Use with caution in asthmatic patients. If a serious reaction occurs, discontinue treatment and institute supportive measures.

• Neurovascular damage: Avoid intra-arterial administration or injection into or near major peripheral nerves or blood vessels since such injections may cause severe and/or permanent neurovascular damage.

• Severe cutaneous adverse reactions: Severe cutaneous adverse reactions (SCAR) (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis) have been reported; discontinue immediately if SCAR is suspected.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended. In the presence of concomitant hepatic impairment, further dosage adjustment may be needed.

• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information

Special populations:

• Neonates: Neonates may have decreased renal clearance of penicillin and require frequent dosage adjustments depending on age.

Other warnings/precautions:

• Electrolyte imbalance: Product contains sodium and potassium; high doses of IV therapy may alter serum levels. If high doses (eg, >10 million units) are used, administer at a slower rate (eg, >30 minutes for intermittent IV infusion).

Geriatric Considerations

Despite a reported prolonged half-life, it is usually not necessary to adjust the dose of penicillin G or VK in the elderly to account for renal function changes with age, however, it is advised to calculate an estimated creatinine clearance and adjust dose accordingly.

Older adults are at increased risk for neurotoxicity (eg, seizures) related to penicillins due to decreased renal clearance or when penicillins are used concurrently with other medications known to decrease the seizure threshold (Schliamser 1991). Seizure activity can present from 12 hours to 9 days post-antibiotic initiation, therefore, monitoring for neurotoxicity is prudent.

It should be noted that the Infectious Diseases Society of America (IDSA) provides guidance on what constitutes a fever in older, long-term care facility residents: A single oral temperature >100°F (37.8°C); or repeated oral temperatures >99°F (37.2°C), or rectal temperatures >99.5°F (37.5°C) or an increase in temperature of >2°F (1.1°C) over the baseline temperature (High 2009).

Pregnancy Considerations

Penicillin G crosses the placenta.

Maternal use of penicillins has generally not resulted in an increased risk of adverse fetal effects.

Penicillin G is the drug of choice for treatment of syphilis during pregnancy and penicillin G (parenteral/aqueous) is the drug of choice for the prevention of early-onset Group B Streptococcal (GBS) disease in newborns (ACOG 782 2019; CDC [Workowski 2015]). When IV therapy is required for anthrax infection in pregnant and postpartum women, penicillin G may be used as an alternative agent (Meaney-Delman 2014).

Breast-Feeding Considerations

Penicillin G is present in breast milk.

In general, antibiotics that are present in breast milk may cause nondose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush or diarrhea (WHO 2002). Peak milk concentrations occur at approximately 1 hour after an IM dose and are higher if multiple doses are given (Greene 1946; Matsuda 1984).

Although the manufacturer recommends that caution be exercised when administering penicillin to breastfeeding women, penicillin is considered compatible with breastfeeding when used in usual recommended doses (WHO 2002).

Lexicomp Pregnancy & Lactation, In-Depth

• Penicillin G (Parenteral/Aqueous)

Briggs' Drugs in Pregnancy & Lactation

• Penicillin G

Adverse Reactions

Frequency not defined:

Cardiovascular: Local thrombophlebitis, localized phlebitis

Central nervous system: Coma (high doses), hyperreflexia (high doses), myoclonus (high doses), seizure (high doses)

Dermatologic: Exfoliative dermatitis, maculopapular rash, skin rash

Endocrine & metabolic: Electrolyte disorder (high doses)

Gastrointestinal: Clostridioides difficile associated diarrhea, Clostridioides difficile colitis

Hematologic & oncologic: Neutropenia, positive direct Coombs test (rare, high doses)

Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction (immediate and delayed), serum sickness-like reaction

Immunologic: Jarisch-Herxheimer reaction

Local: Pain at injection site

Renal: Acute interstitial nephritis (high doses), renal tubular disease (high doses)

Allergy and Idiosyncratic Reactions

• Penicillin Allergy

Metabolism/Transport Effects

Substrate of OAT1/3

Drug Interactions Open Interactions

Acemetacin: May increase the serum concentration of Penicillins. Risk C: Monitor therapy

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination

Dichlorphenamide: Penicillins may enhance the hypokalemic effect of Dichlorphenamide. Risk C: Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy

Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Risk C: Monitor therapy

Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy

Nitisinone: May increase the serum concentration of OAT1/3 Substrates. Risk C: Monitor therapy

Pretomanid: May increase the serum concentration of OAT1/3 Substrates. Risk C: Monitor therapy

Probenecid: May increase the serum concentration of Penicillins. Risk C: Monitor therapy

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification

Teriflunomide: May increase the serum concentration of OAT1/3 Substrates. Risk C: Monitor therapy

Tetracyclines: May diminish the therapeutic effect of Penicillins. Risk C: Monitor therapy

Tolvaptan: May increase the serum concentration of OAT1/3 Substrates. Management: Avoid concomitant use of OAT1/3 substrates in patients receiving the Jynarque brand of tolvaptan. Concentrations and effects of the OAT1/3 substrate would be expected to increase with combined use. Risk D: Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Test Interactions

False-positive or negative urinary glucose determination using Clinitest®; positive Coombs' [direct]; false-positive urinary and/or serum proteins by certain test methods

Monitoring Parameters

Periodic electrolyte, hepatic, renal, cardiac and hematologic function tests during prolonged/high-dose therapy; observe for signs and symptoms of anaphylaxis during first dose. In older adults, especially those with decreased renal function, monitor for seizure activity.

Advanced Practitioners Physical Assessment/Monitoring

Assess culture/sensitivity tests and patient's allergy history prior to beginning therapy. Monitor for signs of anaphylaxis during first dose. Obtain CBC, renal function tests, cardiac function tests, electrolytes, and liver function tests periodically with prolonged or high dose therapy. Test for C. difficile if patient develops diarrhea. Observe for seizures or other neurologic activity, especially in patients with history of seizures. Assess for effectiveness of treatment.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Follow administration guidelines. Monitor closely for signs of hypersensitivity (shortness-of-breath, dyspnea, chest pain, complaints of difficulty swallowing or throat tightness, or change in vital signs). Monitor for severe or bloody diarrhea and send a specimen to the lab for C. difficile. Monitor for improvement of infection. Monitor for CNS adverse events, including seizures or confusion, especially in patients with a history of seizure activity.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous, as potassium [preservative free]:

Generic: 20,000 units/mL (50 mL); 40,000 units/mL (50 mL); 60,000 units/mL (50 mL)

Solution Reconstituted, Injection, as potassium [preservative free]:

Pfizerpen: 5,000,000 units (1 ea); 20,000,000 units (1 ea)

Pfizerpen: 5,000,000 units (1 ea); 20,000,000 units (1 ea) [pyrogen free]

Generic: 5,000,000 units (1 ea); 20,000,000 units (1 ea)

Solution Reconstituted, Injection, as sodium [preservative free]:

Generic: 5,000,000 units (1 ea)

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Injection:

Generic: 1,000,000 units (1 ea); 10,000,000 units (1 ea)

Solution Reconstituted, Injection, as sodium:

Crystapen: 5,000,000 units ([DSC])

Generic: 5,000,000 units (1 ea)

Anatomic Therapeutic Chemical (ATC) Classification

• J01CE01

Generic Available (US)

Yes

Pricing: US

Solution (reconstituted) (Penicillin G Potassium Injection)

5000000 unit (per each): $15.54 - $42.18

20000000 unit (per each): $66.00 - $160.26

Solution (reconstituted) (Penicillin G Sodium Injection)

5000000 unit (per each): $57.60

Solution (reconstituted) (Pfizerpen Injection)

5000000 unit (per each): $15.19

20000000 unit (per each): $60.76

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria

Pharmacodynamics/Kinetics

Distribution: Poor penetration across blood-brain barrier, despite inflamed meninges

Relative diffusion from blood into CSF: Poor unless meninges inflamed (exceeds usual MICs)

CSF:blood level ratio: Inflamed meninges: 2% to 6%

Half-life elimination:

Neonates: <6 days of age: 3.1 hours; ≥14 days of age: 1.4 hours

Adults: Normal renal function: 31 to 50 minutes

End-stage renal disease (ESRD): 6 to 20 hours (Aronoff 2007)

Time to peak, serum: IV: Immediately after infusion

Excretion: Urine (58% to 85% as unchanged drug)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Excretion is delayed.

Hepatic function impairment: When combined with impaired renal function, elimination is further delayed.

Geriatric: Renal clearance may be delayed (caused by decreased renal function).

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Related Information

• Desensitization Protocols

Pharmacotherapy Pearls

1 million units is approximately equal to 625 mg.

Index Terms

Aqueous Crystalline Penicillin G; Benzylpenicillin Potassium; Benzylpenicillin Sodium; Crystalline Penicillin; Penicillin G Potassium; Penicillin G Sodium

References

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Brand Names: International

Benpen (AU, NZ); Pengesod (MX); Penicilina Northia (AR); Penicillin G (BG); Pisacilina (CO); Sodipen (MX)

Last Updated 4/21/20